Investigational Drug
AMG 193
TrialFetch AI Analysis
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Overview
AMG 193 is an oral, brain-penetrant investigational small molecule developed for advanced solid tumors with homozygous MTAP deletion, which occurs in approximately 10%–15% of solid tumors. Early clinical activity was reported in a phase I/II study, but in April 2026 Amgen announced that it would discontinue further development after reviewing emerging clinical data. (pubmed.ncbi.nlm.nih.gov)
AM-9747 is not an alternative name for AMG 193: published medicinal-chemistry research identifies AM-9747 as an earlier lead compound in the program from which AMG 193 was developed. (pubmed.ncbi.nlm.nih.gov)
Mechanism of action
AMG 193 is an MTA-cooperative inhibitor of protein arginine methyltransferase 5 (PRMT5). Loss of MTAP causes methylthioadenosine (MTA) to accumulate and partially suppress PRMT5, making MTAP-deleted cancer cells especially dependent on the remaining PRMT5 activity. AMG 193 preferentially binds and inhibits the MTA-bound PRMT5 complex, producing synthetic lethality while comparatively sparing MTAP-intact cells. Preclinical studies found effects on RNA splicing, DNA-damage responses and cell-cycle progression. (pubmed.ncbi.nlm.nih.gov)
Efficacy
In the peer-reviewed phase I dose-exploration analysis, 80 patients with advanced MTAP-deleted solid tumors received AMG 193. Among 42 response-evaluable patients treated at active and tolerable doses—800 mg once daily, 1,200 mg once daily or 600 mg twice daily—the objective response rate was 21.4% (9/42; 95% CI, 10.3%–36.8%). Responses occurred across eight tumor types, including non-small-cell lung, pancreatic, biliary tract, esophageal, renal-cell and other cancers. (pubmed.ncbi.nlm.nih.gov)
An initial dose-expansion conference report found confirmed response rates of 18.2% in NSCLC (2/11), 12.5% in pancreatic ductal adenocarcinoma (2/16) and 18.2% in biliary tract cancer (2/11) at 800–1,200 mg once daily. Median response duration across responding patients was reported as 8.3 months, although these were small, nonrandomized cohorts. (annalsofoncology.org)
Safety
The most common treatment-related adverse events in dose exploration were nausea (48.8%), fatigue (31.3%) and vomiting (30.0%). Eight patients experienced dose-limiting toxicities, including nausea, vomiting, fatigue, hypersensitivity and hypokalemia. The maximum tolerated dose was 1,200 mg once daily. No clinically significant myelosuppression—the principal limitation of earlier PRMT5 inhibitors—was observed in this analysis. (pubmed.ncbi.nlm.nih.gov)
Further reading
- Phase I clinical results in Annals of Oncology
- Preclinical and translational study in Cancer Discovery
- Medicinal-chemistry discovery of AMG 193
- Phase I dose-escalation and expansion conference abstract
- Amgen announcement discontinuing development
Last updated: Sep 2026
Active trials using AMG 193
Found 3 active trials using this drug:
TrialFetch AI summary: Adults with previously treated, metastatic or unresectable locally advanced NSCLC harboring homozygous MTAP deletion receive oral AMG 193, a brain-penetrant inhibitor of MTA-bound PRMT5. Two dose levels are compared before expansion at the selected dose; there is no standard-treatment control arm.
ClinicalTrials.gov ID: NCT06593522
TrialFetch AI summary: Adults with locally advanced or metastatic NSCLC harboring homozygous MTAP deletion receive AMG 193, a brain-penetrant, MTA-cooperative PRMT5 inhibitor, with treatment selected by histology and molecular features. Combinations include platinum-based chemotherapy plus pembrolizumab, pembrolizumab alone, or sotorasib for KRAS G12C-mutant disease; patients with measurable brain metastases receive AMG 193 alone.
ClinicalTrials.gov ID: NCT06333951
TrialFetch AI summary: Adults with unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma and homozygous MTAP deletion receive AMG 193, an MTA-cooperative PRMT5 inhibitor, with gemcitabine/nab-paclitaxel or modified FOLFIRINOX. A separate cohort with RAS-mutant disease and prior systemic therapy receives AMG 193 with RMC-6236, a multiselective RAS(ON) inhibitor.
ClinicalTrials.gov ID: NCT06360354
